Clinical applications of ultrasound contrast agents

Within the last decade safe and practical ultrasound contrast agents have been introduced. Most of these are based on gas-filled microbubbles, which markedly enhance Doppler signals and, in some cases, also gray-scale images. The clinical improvements expected from ultrasound contrast is reviewed. Tissue-specific contrast agents constitute another area of potential clinical significance. One particular agent is taken up by the reticulo-endothelial system and produces so-called acoustic emission signals when imaged. An introduction to the unique clinical applications of acoustic emission is given. Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of some agents in an attempt to alleviate current limitations of ultrasound contrast studies. Examples of harmonic images are presented.     

Standard properties of ultrasound contrast agents

A standardization procedure for in vitro acoustic characterization of ultrasound contrast agents is presented. One new acoustic parameter for particular importance is retained: This is STAR, scattering-to-attenuation ratio, for quantification of the effectiveness of the contrast agent. The STAR expresses the ability of the contrast agent to enhance the visualization of the tissue containing the contrast agent and, at the same time, represents the degree of its absorption. So, it is desirable to produce a contrast agent with high STAR, having good scattering properties to improve the image visualization, and low attenuation to image the underlying biological structures and to avoid shadowing. In this study, we present methods for calculations and measurements of the STAR and comparison between different contrast agents.     

Twenty-four-hour ambulatory blood pressure evaluation of antihypertensive agents

EVALUATION OF A SMOOTH BLOOD PRESSURE RESPONSE TO TREATMENT: Smooth or uniform blood pressure control is an obvious goal of antihypertensive therapy, but it is difficult to assess by the traditional clinic blood pressure measurements. Ambulatory blood pressure monitoring is therefore increasingly being used to evaluate new antihypertensive drugs and to assess the adequacy of treatment. The use of ambulatory blood pressure monitoring is based on two assumptions: that treatment must be continuously optimal, and that more frequent blood pressure measurements during treatment, particularly at different times and during various types of activity and mental states, may lead to a more accurate assessment than infrequent measurements in the clinic. When ambulatory blood pressure monitoring is used, the effect of a given antihypertensive agent or of a given antihypertensive regimen can be tested on the average blood pressure values over 24 h, or on day- or night-time values. The actual verification of the achievement of a uniform reduction of blood pressure throughout the 24-h time span can be achieved by comparing 24-h blood pressure profiles before treatment and during treatment. The so-called trough: peak ratio is generally used in an attempt at a more quantitative assessment of smooth control. Recently, we have developed the Smoothness Index, defined as the ratio between the mean hourly change in blood pressure (calculated over the 24-h period), divided by the standard deviation of these hourly changes. We have some indication that this may be a more accurate measurement of smooth blood pressure control under therapy than trough: peak ratios. TWENTY-FOUR-HOUR BLOOD PRESSURE CONTROL BY IRBESARTAN: Ambulatory blood pressure assessments are important during the clinical testing of new antihypertensive agents. Our group recently performed a multicenter study to compare the anti-hypertensive effect of three irbesartan dose regimens (75 mg once a day, 150 mg once a day, 75 mg twice a day) and placebo as measured by 24-h ambulatory blood pressure monitoring and confirmed by office blood pressure measurements. All irbesartan regimens were significantly more effective than placebo. Irbesartan at 150 mg once a day provided clinically significant and sustained blood pressure reductions over a full 24 h and had the highest trough: peak ratio and Smoothness Index. No additional benefit was observed with twice-daily dosing using irbesartan at 75 mg compared with a single daily at 150 mg. Therefore irbesartan at a single daily dose of 150 mg offers real efficacy with the potential for greater ease of administration compared with twice-daily antihypertensive therapy.     

Effect of gas-containing microspheres and echo contrast agents on free radical formation by ultrasound

Stabilized microbubbles (microspheres) are widely used to enhance the contrast of ultrasound imaging. Our data provide direct evidence that the contrast agents, Levovist, PVC-AN (polyvinylidene chloride-acrylonitryl copolymer), and Albunex (compared to 5% human albumin), at concentrations comparable to those used for ultrasound imaging, enhance H2O2 production (through the superoxide-dependent pathway) in air-saturated aqueous solutions exposed to 47 kHz ultrasound above the cavitation threshold. These agents also act as scavengers of .H atoms and .OH radicals, thus lowering H2O2 formation (by recombination of .OH radicals) in argon-saturated solutions. EPR spin trapping also reveals that secondary radicals derived from the contrast agents are produced by reactions with .H and .OH which are formed by pyrolysis of water inside cavitation bubbles. In addition, the contrast agents themselves undergo pyrolysis reactions in the cavitation bubbles as demonstrated by formation of methyl radicals. Possible deleterious consequences of the formation of sonochemical intermediates may have to be assessed, particularly since some of the echo contrast agents have been shown to lower the cavitation threshold of diagnostic ultrasound. Unlike the microspheres formed from organic molecules, inorganic microspheres, Eccospheres, because of their stability and inert nature with respect to participation in free radical processes, appear to be suitable tools for enhancing the yields of aqueous sonochemical reactions.     

Doppler ultrasound of blood flow in the hepatic veins

The blood flow in the hepatic veins can normally be studied easily by Doppler ultrasound. The pattern of blood flow in normal individuals is described, and its relation to the cardiac cycle and changing pressure in the right atrium. The blood flow shows variations in healthy persons, and may change in cases of heart disease and hepatic disease. Conditions such as atrial fibrillation, tricuspid regurgitation, abnormal relaxation, restrictive cardiomyopathy, constrictive pericarditis and cardiac tamponade are reflected in the hepatic veins, and the pattern of blood flow may help in diagnosis, and in grading the pathology. In cirrhosis and portal hypertension the heart-synchronous variation in velocity is reduced. This is due to increased resistance to blood flow across the liver and the pressure gradient becoming larger than the variations in pressure in the right atrium.     

Transcutaneous ultrasound augments lysis of arterial thrombi in vivo

BACKGROUND: External ultrasound has a synergistic effect on thrombus disruption with thrombolytic agents in vitro. We hypothesized that transcutaneous ultrasound could augment thrombolysis in vivo. METHOD AND RESULTS: Thrombus formation was induced electrically in 48 pairs of iliofemoral arteries of 24 rabbits; arterial occlusions were documented angiographically. In 17 of 24 rabbits, 25000 units/kg streptokinase was then administered intravenously. The pairs of iliofemoral arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Low-frequency (26 kHz) ultrasound (continuous wave, 18 W/cm2) was applied transcutaneously over the area of occlusion. In 7 of 24 rabbits, 14 thrombotically occluded iliofemoral arteries were exposed to ultrasound alone without streptokinase. The results were evaluated through the use of angiography (TIMI grade flow) and histopathology. After 30 +/- 10 minutes of activated sonication combined with intravenous streptokinase, 10 of 17 iliofemoral arteries (59%) treated with transcutaneous ultrasound were widely patent angiographically, with TIMI grade 3 flow. Histologically, the patent arteries had only minimal focal moral thrombus. The angiographic patency rate was significantly lower in the control groups: 1 of 17 arteries (6%) treated with streptokinase alone (P = .0012) and 1 of 14 arteries (7%) treated with ultrasound alone (P = .0036). CONCLUSIONS: In vivo transcutaneous ultrasound significantly augments lysis of thrombi with streptokinase in rabbit iliofemoral arteries.     

Relation of contrast echo intensity and flow velocity to the amplification of contrast opacification produced by intermittent ultrasound transmission

Intermittent ultrasound transmission during contrast echocardiography, so-called transient response imaging (TRI), amplifies contrast intensity. This effect of TRI is attributed to decreased microbubble destruction by reduced exposure time to ultrasound energy. The present study examined the hypothesis that the signal amplification produced by TRI is related to the baseline intensity present in the image and the velocity of flow. We performed second harmonic (2.5/5.0 MHz) imaging during both continuous (frame rate 55 Hz) and electrocardiogram-triggered TRI mode. Contrast images produced by perfluorohexane microbubbles (AF0150) in a steady flow model were obtained every minute throughout the decay phase at transit velocities of 8.1, 6.2, 3.4, 1.9, and 0.7 cm/sec. The decay of videointensity over time could be fitted to a sigmoid curve for both imaging modes with r > 0.99 for individual velocities. The intensity with TRI was greater than that with continuous imaging (CI) at any time and velocity. The mean increase in intensity between modes throughout decay was 8.2 +/- 3.7, 12.8 +/- 4.2, 25.7 +/- 5.8, 49.5 +/- 8.0, and 64.0 +/- 14.4 gray levels for the respective velocity levels studied (p < 0.0001). Although varying with baseline intensity at early and late phases, the TRI amplification plateaued during middecay, and within the intensity range of 16 to 143 gray levels for CI and 67 to 186 gray levels for TRI, it showed no overlap among the different velocity levels. Thus the ability of TRI to enhance contrast opacification is much greater at low flow velocities, which has implications regarding the mechanism of TRI effect and preferential visualization of intramyocardial coronary arteries by this agent. Although this effect was influenced by the baseline intensity, it was relatively constant for each velocity level within an optimal intensity range during middecay, providing the basis for flow velocity measurement by contrast echo.     

Magnetic resonance contrast agents for neuroimaging. Safety issues

The etiology of the decrease in renal peripheral benzodiazepine receptor (PBR) binding caused by stress was studied in rats. Prior investigations suggest that the response of the renal PBR to stress occurs independently of the hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system. The present experiments tested the hypothesis that the renin-angiotensin system is involved in regulating the PBR. Eighty min of brief, intermittent tailshocks caused increases in plasma renin activity and decreases in renal PBR binding. The stress-induced decrease in renal PBR binding was reversed by pretreatment with captopril. Acute administration of angiotensin II (ANG II) alone caused reductions in PBR binding in kidney, heart, and cerebral cortex. These data suggest that ANG II may be an endogenous factor responsible for regulating the PBR in several tissues during stress.     

Characterization of blood flow turbulence with pulsed-wave and power Doppler ultrasound imaging

Blood turbulence downstream of a concentric 86 percent area reduction stenosis was characterized using absolute and relative Doppler spectral broadening measurements, relative Doppler velocity fluctuation, and Doppler backscattered power. Bidimensional mappings of each Doppler index were obtained using a 10 MHz pulsed-wave Doppler system. Calf red cells suspended in a saline solution were used to scatter ultrasound and were circulated in an in vitro steady flow loop model. Results showed that the absolute spectral broadening was not a good index of turbulence because it was strongly affected by the deceleration of the jet and by the shear layer between the jet and the recirculation zones. Relative Doppler spectral broadening (absolute broadening divided by the frequency shift), velocity fluctuation, and Doppler power indices provided consistent mapping of the centerline axial variation of turbulence evaluated by hot-film anemometry. The best agreement between the hot-film and Doppler ultrasound methods was however obtained with the Doppler back-scattered power. The most consistent bidimensional mapping of the flow characteristics downstream of the stenosis was also observed with the Doppler power index. The relative broadening and the velocity fluctuation produced artifacts in the shear layer and in the recirculation zones. Power Doppler imaging is a new emerging technique that may provide reliable in vivo characterization of blood flow turbulence.     

Hemodynamic tolerance of intravascular contrast agents for magnetic resonance imaging

RATIONALE AND OBJECTIVES: Intravascular contrast agents for magnetic resonance imaging (MRI) facilitate the quantification of tissue perfusion. The authors determined the hemodynamic tolerance of these agents. METHODS: Doses of 0.05, 0.15, and 0.45 mmol/kg of the polymeric intravascular contrast agent gadolinium-DTPA-polylysine, and di-nitrobenzyl-gadolinium-DTPA, a non-polymeric intravascular contrast agent with high protein binding, and gadolinium-DTPA dimeglumine, a paramagnetic contrast agent with extracellular distribution, were injected into 18 normal male rats as a peripheral intravenous bolus. Systolic, diastolic, and mean blood pressure, left ventricular end-diastolic and developed pressure, positive rate of pressure change (+dP/dt), dP/dt, the rate-pressure product, and heart rate were recorded during a period of 20 minutes. Hemodynamic effects were established by analysis of variance for repeated measurements. RESULTS: There was a transient increase of all blood pressure parameters and contractility for Gd-DTPA-polylysine at the dose of 0.45 mmol/kg only. Di-nitrobenzyl-Gd-DTPA increased blood pressure parameters at 0.45 mmol/kg only. At doses of 0.05 and 0.15 mmol/kg, no significant hemodynamic effects were observed. CONCLUSIONS: The authors conclude that Gd-DTPA-polylysine is hemodynamically safe at doses to 0.15 mmol/kg and acts like a plasma expander at higher doses after peripheral bolus injection in normal rats. Additional investigations are indicated to elucidate the mechanism of a nonsignificant and satiable transient hemodynamic depression after injection of 0.05 mmol/kg DNB-Gd-DTPA.     

Validation of a new transit time ultrasound flowmeter for measuring blood flow in colonic mesenteric arteries

OBJECTIVE: To validate a transit time ultrasound flowmeter (CardioMed CM 4000) for measuring blood flow in isolated colonic mesenteric arteries. DESIGN: Experimental and clinical study. SETTING: Teaching hospital, Denmark. ANIMALS AND SUBJECTS: One female pig, and 6 patients being operated on for carcinoma of the sigmoid colon and rectum. INTERVENTIONS: Volume blood flow measured by Cardiomed CM 4000 and pump withdrawal flow recordings. MAIN OUTCOME MEASURES: Correlation between the two methods. RESULTS: There was good agreement between transit time flow recordings and pump withdrawal flow recordings (correlation coefficient of 1.0). Of the differences between the two methods, 95% were between -0.16 ml min(-1) and 1.29 ml min(-1), mean 0.57 ml min(-1), or (in percentages) 105, 95% lying between 97-115. There was also good reproducibility in transit time flow recordings, the mean difference between repeated measurements being 0.06 ml min(-1), 95% lying between -0.66 ml min(-1) and 0.78 ml min(-1). CONCLUSION: Ultrasound transit time flow recordings gave precise measurements of blood flow in isolated colonic mesenteric arteries.     

Noninvasive assessment of collateral blood flow of the cerebral hemisphere by Doppler ultrasound

Directional flow in the frontal artery, a terminal branch of the ophthalmic artery, was assessed nonivasively by Doppler ultrasound druing brief digital compression of the ipsilateral common carotid artery in 62 patients. Directional frontal artery flow during carotid compression was compared with mean distal internal carotid back pressure measured at subsequent carotid endarterectomy. Mean carotid back pressure in 28 patients with normal frontal artery flow direction during carotid compression, 68 +/- 14 millimeters of mercury, was significantly higher than that observed in 24 patients in whom frontal artery flow was completely obliterated and ten in whom frontal artery flow was reversed. Distal internal carotid back pressure exceeded 48 millimeters of mercury in all patients with normal frontal artery flow direction during carotid compression. Conversely, carotid back pressure was below 41 millimeters of mercury in all but one patient in whom frontal artery flow was obliterated or bliterated or reversed during carotid compression. The results of this study indicate that Doppler ultrasound assessment of frontal artery flow direction during simultaneous carotid compression provides a rapid, sale noninvasive estimate of the adequacy of collateral hemispheric circulation.     

Sonographic detection of tumor blood flow using a new contrast agent in woodchuck hepatomas

The aim of this study was to assess the ability of perfluoropropane-filled albumin microspheres to visualize tumor blood flow in woodchuck hepatomas. Ten tumors in five woodchucks with hepatomas were imaged before and after intravenous injection (dosages of 0.01 ml/kg to 2.0 ml/kg) of an agent using color Doppler sonography and gray scale ultrasonography. Both enhanced imaging modalities demonstrated blood flow around and within all tumors. Enhanced gray scale ultrasonography demonstrated sonographic "tumor blush" in seven tumors (70%). In conclusion, tumor blood flow in woodchucks was visualized more clearly using the agent on both color Doppler and gray scale ultrasonography.     

Strain gauge plethysmography and Doppler ultrasound in the measurement of limb blood flow

The maintenance of adequate oxygen delivery (DO2) and tissue uptake (VO2) has become central dogma in the management of the critically ill. However, these parameters are derived using gas tensions measured in mixed venous blood and may not reflect changes in regional blood flow. Therefore, it has become necessary to provide estimates of blood flow to specific organs and to evaluate the most adequate techniques available. In order to define the best means of assessing blood flow to the lower limb noninvasively in normal subjects, measurements of superficial femoral arterial blood flow using Doppler ultrasound (DU) and strain gauge plethysmography (SGP) were compared in 10 normal volunteers at rest and during exercise. To evaluate the effect of strain gauge positioning, results of measurements made under four different combinations of cuff/strain gauge placement were compared in 15 other volunteers. The correlation of the limb blood flow obtained using the two methods at rest and exercise was 0.57 and 0.62 and the limits of agreement (d +/- 2SD) were 0.40 +/- 2.49 and -0.86 +/- 5.22 ml 100 ml-1 tissue min-1 at rest and on exercise, respectively. Results obtained using SGP were more reproducible (Coef. repeat. 0.45 vs. 0.94 ml 100 ml-1 tissue min-1, for SGP and DU, respectively). The various combinations of cuff/strain gauge positioning showed a tendency to over-read when the latter was placed on the thigh, but were not significantly different (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental ultrasound contrast study of the myocardium]

The ultrasound contrast medium obtained by the original methods was administered into the left ventricular cavity and myocardium of 12 open-chest dogs by using a catheter. After its administration into the cavity there was its intensive contrast. When the ultrasound contrast was administered into the aortic root, the entire myocardium contrasted, on selective administrations of the contrast into the coronary arteries, the beds supplied by appropriate arteries contrasted. The ultrasound contrast study enabled the areas with impaired perfusion as echo-negative "filling defects" to be detected and mapped. The imaging of myocardial blood flow in tomographic sections and real time allows one to regard it promising for clinical use.     

Quantification of blood echogenicity: evaluation of a semiquantitative method of grading spontaneous echo contrast

Spontaneous echo contrast (SEC) is an echogenic, swirling pattern of blood flow which may be observed by transesophageal echocardiography (TEE) in the left atrium in low flow states, such as atrial fibrillation (AF). The presence of SEC has been proposed as a marker of increased thromboembolic risk. Evaluation of the severity of SEC might be useful in stratification of thromboembolic risk. The aim of this study was to validate a semiquantitative method of grading SEC against quantitative videodensitometric analysis. TEE studies were performed in 50 patients with AF. The severity of left atrial SEC was graded by three independent observers and by videodensitometry. There was a strong, positive correlation between the semiquantitative grades of SEC and quantitative videodensitometric scores (r = 0.85, P < 0.0001). Inter- and intraobserver correlations in the grading of SEC were very high (observer 1 vs. 2: r = 0.98, P = 0.0001; observer 1 vs. 3: r = 0.93, P = 0.0001; observer 1 vs. 1: r = 0.97, P = 0.0001). Semiquantitative grading of SEC can be performed rapidly and reliably by experienced observers. These results support the use of semiquantitative grading in studies of the pathogenesis and prognostic implications of SEC.     

Doppler ultrasound investigation of uterine and ovarian blood flow in infertility and early pregnancy

This review describes the current use of Doppler ultrasound to examine blood flow in the uterus and ovaries in infertile patients and during early pregnancy. The basics of Doppler ultrasound and the different methods of measuring blood flow are discussed from the viewpoint of the clinician who may be unfamiliar with Doppler physics and terminology. Normal values in the menstrual cycle and the relationship of uterine and ovarian blood flow to infertility and to implantation following in-vitro fertilization are presented. Normal values for uterine blood flow in the first 16 weeks of pregnancy and the effect of sex steroids and ovulation induction on their values are described. The possible relationship of defective uterine blood flow to recurrent abortion is examined. New areas of investigation, such as the effect of standing on blood flow, and the effect of drugs are explored. The findings of this review indicate that Doppler blood flow studies may provide significant information about possible causes of some disorders of infertility and early pregnancy and methods of treatment for the same.     

The complement-activating action of modern x-ray contrast agents

The study conducted proved that triombrast (dose dependently) > hexabrics > Ultravist > or = melitrast = omnipac in a concentration interval of 0.03-30.0 mg iodine/ml in vitro and in a dose interval of 0.5-2.0 g iodine/kg in vivo activate the complement system (CS) according to the alternative way in the blood of "sensitive" rats. The degree of CS activation by radiopaque agents (ROA) is significantly determined mathematically by their viscosity and relation of the number of iodine atoms to the number of ions or dissolved particles, and by their hydrophilic (for nonion CS) and osmotic (for ion monomeric CS) properties.